Novel salts of selective estrogen receptor degraders

Abstract

Provided herein are compounds, salts, crystalline forms, and pharmaceutical compositions that are related to Selective Estrogen Receptor Degraders, as well as methods of preparing the same. Also provided herein are methods of using the compounds, salts, crystalline forms, and pharmaceutical compositions for the treatment of diseases or disorders, such as breast cancer.

What is claimed is: 
     
         1 . A meglumine salt of Compound FA represented by the structure below: 
       
         
           
           
               
               
           
         
       
     
     
         2 . The meglumine salt of  claim 1 , which is in a crystalline Form I, characterized by (1) an X-ray powder diffraction (XRPD) pattern having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or 8) of the following peaks: 4.7, 9.1, 10.0, 17.6, 18.2, 19.0, 21.5, and 23.7 degrees 2 theta, ±0.2°; (2) an X-ray powder diffraction (XRPD) pattern having one or more (e.g., 8 or more, 12 or more, 16 or more, or 20 or more) of the following peaks: 4.7, 9.1, 10.0, 11.3, 13.0, 13.3, 13.5, 15.1, 16.4, 17.6, 18.2, 18.8, 19.0, 20.0, 20.4, 21.5, 22.4, 23.7, 23.9, 24.9, and 25.3 degrees 2 theta, ±0.2°; (3) an XRPD pattern substantially the same as shown in  FIG.  1 A ; (4) a Differential Scanning calorimetry (DSC) pattern substantially the same as shown in  FIG.  1 B ; or any combination thereof (e.g., (1) and (4), (2) and (4), or (3) and (4)). 
     
     
         3 . The meglumine salt of  claim 1 , which is in a crystalline form II, characterized by (1) an X-ray powder diffraction (XRPD) pattern having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) of the following peaks: 8.0, 12.0, 12.4, 16.1, 17.2, 19.7, 22.1, 22.5, and 23.9 degrees 2 theta, ±0.2°; (2) an X-ray powder diffraction (XRPD) pattern having one or more (e.g., 8 or more, 12 or more, or 16 or more) of the following peaks: 4.0, 8.0, 10.3, 12.0, 12.4, 14.7, 14.9, 15.5, 16.1, 17.2, 19.7, 20.8, 22.1, 22.5, 23.9, 24.5, 24.8, and 26.3 degrees 2 theta, ±0.2°; (3) an XRPD pattern substantially the same as shown in  FIG.  2 A ; (4) a Differential Scanning calorimetry (DSC) pattern substantially the same as shown in  FIG.  2 B ; or any combination thereof (e.g., (1) and (4), (2) and (4), or (3) and (4)). 
     
     
         4 . The meglumine salt of  claim 1 , which is in a crystalline form III, characterized by (1) an X-ray powder diffraction (XRPD) pattern having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17) of the following peaks: 7.5, 10.2, 12.0, 14.5, 15.6, 17.0, 17.4, 19.2, 19.7, 20.6, 21.5, 22.0, 22.5, 23.8, 24.6, 24.9, and 28.1 degrees 2 theta, ±0.2°; (2) an X-ray powder diffraction (XRPD) pattern having one or more (e.g., 8 or more, 12 or more, 16 or more, 20 or more, or 24 or more) of the following peaks: 3.7, 6.4, 7.5, 10.2, 11.2, 12.0, 14.5, 15.6, 17.0, 17.4, 17.8, 19.2, 19.7, 20.3, 20.6, 21.5, 22.0, 22.5, 22.8, 23.8, 24.6, 24.9, 25.5, 25.9, 26.5, 28.1, 30.9, and 31.4 degrees 2 theta, ±0.2°; (3) an XRPD pattern substantially the same as shown in  FIG.  3 A ; (4) a Differential Scanning calorimetry (DSC) pattern substantially the same as shown in  FIG.  3 B ; or any combination thereof (e.g., (1) and (4), (2) and (4), or (3) and (4)). 
     
     
         5 . A pharmaceutical composition comprising the meglumine salt of any one of  claims 1 - 4 , and optionally a pharmaceutically acceptable excipient. 
     
     
         6 . The pharmaceutical composition of  claim 5 , which is free or substantially free of Compound FA in free acid form. 
     
     
         7 . The pharmaceutical composition of  claim 5  or  6 , comprising the meglumine salt of  claim 2 , wherein the pharmaceutical composition is free or substantially free of Compound FA in a salt form other than meglumine salt. 
     
     
         8 . The pharmaceutical composition of any one of  claims 5 - 7 , comprising the meglumine salt of  claim 2 , wherein the pharmaceutical composition is free or substantially free of meglumine salt of Compound FA in a crystalline form other than Form I. 
     
     
         9 . The pharmaceutical composition of  claim 5  or  6 , comprising the meglumine salt of  claim 3 , wherein the pharmaceutical composition is free or substantially free of Compound FA in a salt form other than meglumine salt. 
     
     
         10 . The pharmaceutical composition of any one of  claim 5 ,  6 , or  9 , comprising the meglumine salt of  claim 3 , wherein the pharmaceutical composition is free or substantially free of meglumine salt of Compound FA in a crystalline form other than Form II. 
     
     
         11 . The pharmaceutical composition of  claim 5  or  6 , comprising the meglumine salt of  claim 4 , wherein the pharmaceutical composition is free or substantially free of Compound FA in a salt form other than meglumine salt. 
     
     
         12 . The pharmaceutical composition of any one of  claim 5 ,  6 , or  11 , comprising the meglumine salt of  claim 4 , wherein the pharmaceutical composition is free or substantially free of meglumine salt of Compound FA in a crystalline form other than Form III. 
     
     
         13 . The pharmaceutical composition of any one of  claims 5 - 12 , further comprising meglumine salt of Compound FA in an amorphous form. 
     
     
         14 . A method of treating a proliferative disease, the method comprising administering to a subject in need thereof an effective amount of the meglumine salt of any one of  claims 1 - 4  or the pharmaceutical composition of any one of  claims 5 - 13 . 
     
     
         15 . The method of  claim 14 , wherein the proliferative disease is cancer. 
     
     
         16 . A method of treating breast cancer and/or a gynecological disease or cancer, the method comprising administering to a subject in need thereof an effective amount of the meglumine salt of any one of  claims 1 - 4  or the pharmaceutical composition of any one of  claims 5 - 13 . 
     
     
         17 . A method of treating ER+ breast cancer and/or a gynecological disease or cancer associated with ER, the method comprising administering to a subject in need thereof an effective amount of the meglumine salt of any one of  claims 1 - 4  or the pharmaceutical composition of any one of  claims 5 - 13 . 
     
     
         18 . The method of any one of  claims 14 - 17 , further comprising administering to the subject an effective amount of an additional antiproliferative agent. 
     
     
         19 . The method of  claim 17  or  18 , wherein the method is for treating ER+ breast cancer. 
     
     
         20 . A method of preparing Compound FA or an amine salt thereof, the method comprising:
 a) reacting a tryptamine compound,   
       
         
           
           
               
               
           
         
       
       or a salt thereof, with an aldehyde, 
       
         
           
           
               
               
           
         
       
       or a salt thereof, under suitable conditions to form Compound FA 
       
         
           
           
               
               
           
         
       
       or a salt thereof;
 b) optionally converting Compound FA or a salt thereof into an amine salt of Compound FA. 
 
     
     
         21 . The method of  claim 20 , wherein the amine salt is a diisopropylethyl amine salt, and the method comprises reacting Compound FA or a salt thereof with diisopropylethyl amine to provide the diisopropylethyl amine salt of Compound FA: 
       
         
           
           
               
               
           
         
       
     
     
         22 . The method of  claim 20 , wherein the amine salt is a meglumine amine salt, and the method comprises reacting Compound FA or a salt thereof with meglumine to provide the meglumine salt of Compound FA: 
       
         
           
           
               
               
           
         
       
     
     
         23 . The method of  claim 22 , comprising reacting a diisopropylethyl amine salt of Compound FA with meglumine to provide the meglumine salt of Compound FA. 
     
     
         24 . The method of any one of  claims 20 - 23 , wherein the tryptamine compound is prepared by a process comprising reacting 
       
         
           
           
               
               
           
         
         with 
       
       
         
           
           
               
               
           
         
         in the presence of a base. 
       
     
     
         25 . The method of  claim 24 , wherein the 
       
         
           
           
               
               
           
         
         is prepared by a process comprising reducing 
       
       
         
           
           
               
               
           
         
         with a reducing agent to form an alcohol 
       
       
         
           
           
               
               
           
         
         and subsequently reacting the alcohol with a triflate donor agent to form 
       
       
         
           
           
               
               
           
         
       
     
     
         26 . The method of  claim 24 , wherein the 
       
         
           
           
               
               
           
         
         is prepared by a process comprising reacting 
       
       
         
           
           
               
               
           
         
         with a fluoride (e.g., HF/pyridine) to form an alcohol 
       
       
         
           
           
               
               
           
         
         and subsequently reacting the alcohol with a triflate donor agent to form 
       
       
         
           
           
               
               
           
         
       
     
     
         27 . The method of any one of  claims 20 - 26 , wherein the aldehyde is prepared by a process comprising converting a dichloro-compound 
       
         
           
           
               
               
           
         
         into an anionic intermediate with a base, which is subsequently reacted with an aldehyde donor agent to form 
       
       
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
         28 . A product produced by any one of  claims 20 - 27 .